PROJECT ABSTRACT Cancer exhibits significant sex differences in both incidence and mortality; more men develop cancer, and more men die from cancers overall. The magnitude of these sex differences in incidence and mortality differs by cancer. Specifically for malignant central nervous system tumors, the majority of which are gliomas (where glioblastoma (GBM) is the most common type), and for head and neck cancers, we see drastic differences in incidence and mortality. Using the most recent data available from the United States Cancer Statistics, males have a higher incidence and mortality compared to females. In general, sex differences are not accounted for in the majority of experimental models, not considered in the treatment of either malignant CNS tumors or head and neck cancers, nor accommodated in clinical trial design. In response to PA-19-165, administrative supplement for research on sex-gender influences, we will leverage extensive and comprehensive clinical data from NRG-Oncology clinical trials in glioblastomas and head and neck cancers in order to study the influence of sex on response to treatment. We are motivated by the potential of sex differences research to improve cancer treatments. This administrative supplement builds on our published observations of sex differences in GBM incidence and outcome, GBM and non-GBM genetic risk, and GBM oncogenic pathways and is led by established investigators with complementary expertise and a strong collaborative history. This project will use data from 2 recent NRG-Oncology clinical trials in GBM, the most common type of malignant CNS tumor, and 3 recent NRG-Oncology clinical trials in head and neck cancer to study sex-stratified models of treatment response and sex-treatment interactions. This administrative supplement aligns well with the parent Case Comprehensive Cancer Center Support Grant (P30 CA043703, PI: Gerson) as it leverages initiatives in the Cancer Center in sex differences in brain tumors (led by Drs. Barnholtz-Sloan and Lathia), molecular oncology, population science and developmental therapeutics (novel clinical trials focused on brain tumors and head and neck cancers). We hypothesize that sex stratifies response to treatment and overall survival for patients enrolled on specific NRG-Oncology clinical trials with GBM and head and neck cancers and that sex may in fact directly interact with treatment response. We will address our hypothesis via the following Specific Aims: SPECIFIC AIM 1: To delineate sex differences in response to treatment and overall survival for patients diagnosed with GBM and enrolled in NRG-Oncology clinical trials 05-25 and 08-25 and develop sex-specific nomograms for overall survival (OS). SPECIFIC AIM 2: To delineate sex differences in response to treatment and overall survival and sex-treatment interactions for patients diagnosed with head and neck cancer and enrolled in NRG-Oncology clinical trials 10-16, 05-22 and 01-29 and develop sex-specific nomograms for overall survival (OS).